Immune thrombocytopenia (ITP), a common autoimmune disease, affects a large population of individuals worldwide; in the U.S. alone, as many as 33,000 new cases occur each year. Approximately 25-30 percent of chronic ITP patients are refractory to standard therapy (corticosteroid immunosuppression and splenectomy), and are at high risk for fatal hemorrhage. No feasible alternative therapies are presently available. Progress toward the development of new treatments has been impeded by difficulties associated with conducting investigations in ITP patients and by the unavailability of suitable animal models of the disease. A primary significance of this proposal lies in its potential to develop mechanistically relevant, quantitative animal models of immune thrombocytopenia. Extremely promising results have been obtained in our laboratory in the development of passive and active animal models of ITP. Further validation and complete development of these experimental models, as proposed in Aim number 1, will permit, for the first time, quantitative evaluation of the efficacy of existing and new therapies. The project plans to take the advantage of the animal models to examine hypotheses regarding the mechanisms of action of an effective, yet unfeasible therapy of chronic ITP, pooled immunoglobulin (IVIG, Aim number 2). Delineation of the pathways by which IVIG achieves effects may lead to the development of new therapies with improved pharmaceutical and therapeutic characteristics. Furthermore, the proposal plans to develop and test two new therapies for ITP: (1) a novel bioreactor for the antigen-specific removal of pathogenic antibodies (Aim number 3), which is expected to carry significant advantages over clinically approved methods for ITP treatment (e.g., Protein A immuno- adsorption); and (2) a new liposomal immunotherapy (Aim number 4), designed to improve upon anti-Rho(D) immunotherapy, which is approved for use in non-splenectomized ITP patients as an inhibitor of auto-antibody mediated elimination of platelets. Findings gathered from the body of proposed studies may offer insight in the design of effective combination therapy for treating ITP and other autoimmune diseases, which, as a group, affect over 50 million Americans.